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Identification of a family with van der Hoeve’s syndrome harboring a novel COL1A1 mutation and generation of patient-derived iPSC lines and CRISPR/Cas9-corrected isogenic iPSCs

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Abstract

Van der Hoeve’s syndrome, also known as osteogenesis imperfecta (OI), is a genetic connective tissue disorder characterized by fragile, fracture-prone bone and hearing loss. The disease is caused by a gene mutation in one of the two type I collagen genes COL1A1 or COL1A2. In this study, we identified a novel frameshift mutation of the COL1A1 gene (c.1607delG) in a family with OI using whole-exome sequencing, bioinformatics analysis and Sanger sequencing. This mutation may lead to the deletion of a portion of exon 23 and the generation of a premature stop codon in the COL1A1 gene. To further investigate the impact of this mutation, we established two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of OI patients carrying a novel mutation in the COL1A1 gene. Osteoblasts (OB) derived from OI-iPSCs exhibited reduced production of type I collagen and diminished ability to differentiate into osteoblasts. Using a CRISPR-based homology-directed repair strategy, we corrected the OI disease-causing COL1A1 novel mutations in iPSCs generated from an affected individual. Our results demonstrated that the diminished expression of type I collagen and osteogenic potential were enhanced in OB induced from corrected OI-iPSCs compared to those from OI-iPSCs. Overall, our results provide new insights into the genetic basis of Van der Hoeve’s syndrome and highlight the potential of iPSC technology for disease modeling and therapeutic development.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

The reported study was supported by National Natural Science Foundation of China (Grant no. 82071065); the Major State Basic Research Development Program of China (973 Program) (Grant no. 2014CB541702); the National Key Research and Development Program of China (Grant no. 2020YFC2005204); the Hunan Provincial Key Research and Development Program (Grant no. 2020SK2106); the Startup Project of University of South China (Grant no. 201RGC002); the Fundamental Research Funds for the Central Universities of Central South University, China (Grant no. 2021zzts0345; CX20210355); China Postdoctoral Science Foundation (Grant nos. 2021M693566, 2021T140751); the science and technology innovation Program of Hunan Province China (Grant nos. 2020RC2013); Hunan Province Natural Science Foundation (Grant nos. 2021JJ41017, 2021JJ31084); the Foundation of Hunan Provincial Health Commission (no. 202107010047).

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Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

    SiJun Li, Lingyun Mei, Chufeng He, Xinzhang Cai, Hong Wu, XueWen Wu, Yalan Liu, Yong Feng & Jian Song

  2. Department of Otorhinolaryngology, The Affiliated Maternal and Child Health Hospital of Hunan Province, Hengyang Medical School, University of South China, Changsha, Hunan, China

    Yong Feng

  3. Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China

    SiJun Li, Lingyun Mei, Chufeng He, Xinzhang Cai, Hong Wu, XueWen Wu, Yalan Liu & Jian Song

  4. Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, Hunan, China

    SiJun Li, Lingyun Mei, Chufeng He, Xinzhang Cai, Hong Wu, XueWen Wu & Yalan Liu

  5. MOE Key Lab of Rare Pediatric Diseases and Institute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, Hunan, China

    Yong Feng

  6. National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Jian Song

Authors
  1. SiJun Li
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  2. Lingyun Mei
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  8. Yong Feng
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Contributions

SL: Data curation, Writing-Original draft preparation and performing experiments. CH: acquisition and analysis of data. LM: Software, Validation. YL: Visualization. HW: Investigation. XW: Methodology. XC: Data curation. JS: Contribute to revising the manuscript critically for important intellectual content. YF: Conception and Design and Supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yong Feng or Jian Song.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The experimental protocol was established according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Xiangya Hospital, Central South University approved the study (no. 201703408); The animal study was approved by Xiangya Hospital, Central South University Experimental Animals Ethics Committee and performed in accordance with the Animal Experimentation Policy (Number: 201703409).

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Li, S., Mei, L., He, C. et al. Identification of a family with van der Hoeve’s syndrome harboring a novel COL1A1 mutation and generation of patient-derived iPSC lines and CRISPR/Cas9-corrected isogenic iPSCs. Human Cell 37, 817–831 (2024). https://doi.org/10.1007/s13577-024-01028-3

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